Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS), which causes demyelination of axons. Experimental autoimmune encephalomyelitis (EAE) is a mouse model of MS that is induced by immunizing mice with myelin oligodendrocyte glycoprotein (MOG). The best-known treatment for MS is the type I interferon (IFN), IFN-β; however, its mechanism of action is unclear. Prinz etal. found that the abundance of IFN-β was increased in the CNS of MOG-treated mice compared with untreated mice, as measured by enzyme-linked immunosorbent assays, suggesting that local, but not systemic, IFN-β abundance is important in this disease. Treatment of mice deficient in the type I IFN receptor (Ifnar–/– mice) with MOG resulted in worse disease and increased mortality compared with MOG-treated wild-type mice. Histological examination revealed that MOG-treated Ifnar–/– mice had more infiltrating myeloid cells, which included macrophages and microglia, in their spinal cords than did MOG-treated wild-type mice. The authors bred strains of mice that were Ifnar-deficient in specific cell types and exposed them to MOG. Whereas deletion of Ifnar in CD4+ T cells, B cells, astrocytes, or oligodendrocytes had little or no effect on disease outcome, deletion of Ifnar in myeloid cells led to exacerbated disease and increased mortality compared with that in wild-type mice. This was associated with the increased uptake of degraded myelin protein by Ifnar-deficient myeloid cells and the increased abundance of the proinflammatory cytokine tumor necrosis factor-α and the chemokine CCL2, which recruits myeloid cells. As Axtell and Steinman discuss, this study suggests that IFN-β acts on myeloid cells in the CNS to suppress inflammation and the processing of antigenic peptides, which would otherwise exacerbate disease by activating infiltrating T cells and causing further inflammation.